PPARy plays a critical role in adipocyte differentiation and glucose metabolism, and thus provides a potential link between obesity and diabetes. The goal of this proposal is to examine the effect of phosphorylation on the metabolic and physiological actions of the nuclear receptor PPARy. This will be accomplished by studying metabolic parameters such as insulin sensitivity and glucose metabolism in mice whose PPARy has been mutated to mimic the less active, phosphorylated state (PPARy-S112D) in the setting of diet-induced obesity. Specific Aim 1 is to determine the effect of PPARy phosphorylation on glucose homeostasis and insulin resistance in the setting of diet-induced obesity. We hypothesize that PPARy-S112D mice will have impaired glucose homeostasis and increased insulin resistance relative to wild type littermates in the setting of diet-induced obesity. This will be tested by performing provocative metabolic tests and by analyzing expression of key hormones and cytokines involved in insulin resistance and glucose metabolism. Specific Aim 2 is to determine the effect of PPARy phosphorylation on weight gain and body composition during diet-induced obesity. We hypothesize that PPARy-S1 12D mice will be protected against weight gain when placed on a high fat diet, concomitant with less adipose mass than their wild type littermates. This will be determined by performing measurements of body weight on normal chow and during diet induced obesity, performing non-invasive body fat distribution measurements, and monitoring food intake, energy expenditure and respiratory quotient. These studies will provide insight into the role of phosphorylation of PPARy in metabolic processes, and may provide insight into the development of selective PPARy modulators that elicit the beneficial effects of PPARy activation but with fewer deleterious side effects, which would therefore be beneficial in the treatment of type 2 diabetes